Clinical characterization and detection of subclinical atherosclerosis in subjects with extreme hyperalphalipoproteinemia. / Caracterización clínica y detección de arteriosclerosis subclínica en sujetos con hiperalfalipoproteinemia extrema.

INTRODUCTION AND OBJECTIVES: The association between HDL cholesterol (HDL-C) levels and death from cardiovascular disease follows a U-shaped pattern, increasing at the extremes. The objective of the study was to characterize a sample of subjects with extreme hyperalphalipoproteinemia (HAE). MATERIAL AND METHODS: 53 cases with HAE were recruited, 24 women (HDL-C>135mg/ dL) and 29 men (HDL-C>116mg/ dL). A detailed medical history was taken and questionnaires on adherence to the Mediterranean diet and physical activity were collected. Carotid ultrasounds were performed to detect the presence of suclinical atherosclerosis. RESULTS: The most prevalent cardiovascular risk factor (CVRF) was dyslipidemia (64%) with no significant differences between men and women, unlike hypertension (21% in women, versus 55% in men, p=0.01) and others CVRF, for example, diabetes. 7% of the series had previous cardiovascular disease, women had higher LDL cholesterol (p=0.002) and HDL-C than men (without significant differences). Plaque was detected in 53% of cases, being more prevalent in men. Patients with plaque were older, drank more alcohol and smoked more (p<0.05). CONCLUSIONS: Men had a higher prevalence of CVRF than women, except for dyslipidemia. Subclinical atherosclerosis occurred in more than half of the series. Age, alcohol consumption and smoking were independently associated with the presence of plaque, however, our data do not show a significant influence of HDL-C levels.

Diabetes mellitus, malnutrition, and sarcopenia: The bond is not explained by bioelectrical impedance analysis in older adults.

As people age, their risk of diabetes mellitus (DM) and sarcopenia increases due to the decline in muscle mass and strength. Bioelectrical impedance analysis (BIA) is a method used to detect changes in body composition. The primary aim of the study was to determine the distribution of BIA variables among a group of non-DM people and two groups of patients with controlled and uncontrolled DM. The secondary aim was to establish the independent association between BIA-derived data, lipidic assets, and the prevalence of metabolic syndromes with DM. This study included a total of 235 participants who were categorized into three groups based on the presence of diabetes mellitus (DM) and their glycated hemoglobin (HbA1c) levels: non-DM, controlled DM (HbA1c≤7.0%), and uncontrolled DM (HbA1c>7.0%). Waist circumference (p=0.005), bone (p<0.001), muscular (p<0.001), and appendicular skeletal mass (p<0.001) were lower in the non-DM group, while sarcopenic risk (p<0.001), total cholesterol (p<0.001), and LDL (p<0.001), were higher. Grip strength (p<0.001), visceral fat (p=0.01), and phase angle (p=0.04) were significantly lower in non-DM than uncontrolled DM patients, as well as the number of drugs taken (p=0.014). A multivariate analysis highlighted that LDL (coefficient -0.006, p=0.01) was negatively associated, while bone mass (coefficient 0.498, p=0.0042) was positively associated with DM uncontrol. Our study shows that BIA may not be the ideal tool for distinguishing between elderly individuals with and without DM, as it can be affected by numerous covariates, including potential differences in glucometabolic and cardiovascular control.

Recurrent stroke syndrome without abnormality on magnetic resonance imaging caused by stenosis of middle cerebral artery: A case report.

Middle cerebral artery stenosis is the leading and the most frequent cause of stroke due to intracranial stenosis in Asia. Magnetic resonance imaging (MRI) is more sensitive than computed tomography of the head for detecting acute brain ischemia. We are reporting a case of a 28-year-old female with recurrent left hemiparesis. After the last attack, an improvement in motor function was seen in less than 24 hours. Though the restoration of motor functions is not complete yet, an MRI scan that was done two weeks later appeared normal. Ischemic stroke in middle cerebral artery stenosis is associated with hemodynamic stroke due to hypoperfusion or lack of blood flow to brain tissue. Recurrent strokes can be prevented by better medical management in patients through regulation and management of risk factors.

Evaluation of the antiparasitic activity of the chitosan-silver nanocomposites in the treatment of experimentally infested pigeons with Pseudolynchia canariensis.

This study aimed to evaluate the efficacy of chitosan-silver nanocomposites in the treatment of experimentally infested pigeons with Pseudolynchia canariensis (P. canariensis) with evaluation of different immunological parameters before and after treatment. Therefore, fourteen birds were divided into 2 groups; group1(infested group including 12 birds) which subdivided into 6 sub-groups experimentally infested pigeons 2 pigeons each, and five group of them were treated with chitosan-silver nanocomposites and sub-group number 6 was treated with deltamethrin while, group 2 including two pigeons were kept as control negative ones. P. canariensis flies distributed under the wing and /or under the tail in infested group and these pigeons showed significantly lower RBCs and higher WBCs than that in non-infested pigeons. The cell mediated immune response against experimentally infested pigeons with P. canariensis was studied. P. canariensis infestation in pigeons have a negative impact on pigeon's blood parameters, increase TNF-α and IL-1ß cytokines levels. This study cleared out the role of P. canariensis in the induction of a case of oxidative stress indicated by high level of nitric oxide and malondialdehyde (MDA) with low antioxidant capacity in shape of reduced zinc concentration in the sera of experimentally infested pigeon. Chitosan-silver nanocomposite has a promising effect in the elimination of P. canariensis infestation in pigeons.

Infection and food combine to cause atherosclerotic coronary heart disease - Review and hypothesis.

HYPOTHESIS: It is hypothesised that a combination of childhood and later life infections and excess food consumption, particularly of Western style food, initiates and contributes to atherosclerotic coronary heart disease. To consider this hypothesis we have conducted a brief review of the role of childhood infections, food, and their combined influence on atherosclerosis. EVIDENCE: (i) Studies of populations with high prevalence of infections and low "hunter gather" like food consumption, have extremely low prevalence of atherosclerosis, (ii) there are consistent associations between infections in childhood and adult atherosclerotic coronary heart disease, (iii) there is an association between increased body weight, (an indication of excess eating), and atherosclerotic heart disease, and (iv) there is evidence that a combination of increased body weight and infections influences the development of atherosclerotic coronary heart disease.Infections do not appear to act independently to cause atherosclerosis. A combination of both food and infection appears to be required to cause atheroma. CONCLUSION: The hypothesis that infections when combined with excess eating initiates atherosclerosis, is plausible. ACTION: Action aimed at prevention of atherosclerotic heart disease is possible. There are three safe approaches to prevention (i) encouragement of Mediterranean like diets, (ii) avoidance of overeating and (iii) vigorous control of infections among all age groups. There is a need to monitor patients with a history of serious childhood infections and poor nutrition. In addition, for high risk subjects, cholesterol lowering statins are of proven and safe value.

Psidium guajava Linn leaf ethanolic extract: In vivo giardicidal potential with ultrastructural damage, anti-inflammatory and antioxidant effects.

INTRODUCTION AND AIM: Considering the magnitude of giardiasis problem, the side-effects of the used anti-giardia drugs and the resistance posed against them, the current study aimed to evaluate the in-vivo giardicidal effect of Psidium guajava leaf extract (PGLE). METHODS: For fulfilling this aim, five Swiss-albino mice groups were included; GI: non-infected, GII: Giardia-infected and non-treated, GIII: Giardia-infected and metronidazole-treated, GIV: Giardia-infected and PGLE-treated, and GV: Giardia-infected and treated with both metronidazole and PGLE. Treatment efficacy was assessed via; Giardia cyst viability and trophozoite count, trophozoite electron microscopic ultrastructure, duodenal histopathological scoring, immunohistochemistry for TNF-α and duodenal scanning electron microscopy. Moreover, mice serum liver enzymes, total bilirubin, albumin, lipid profile including; total cholesterol, HDL, LDL and triglycerides were assessed. Additionally, hepatic oxidative stress markers including; malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH) and superoxide dismutase (SOD) were measured. RESULTS: Results showed that PGLE whether alone or combined with metronidazole has induced significant trophozoite count reduction and major architectural changes. Duodenal histological improvement, and local protective anti-inflammatory effect were confirmed. PGLE has also helped in healing of Giardia-induced gut atrophy. Thus, offered a comprehensive therapy for both the pathogen and the resultant pathological sequalae. Serum markers showed favorable hepatoprotective effect. Total cholesterol, LDL and triglycerides levels were less in PGLE-treated group than in metronidazole-treated group. Hepatic oxidative stress markers revealed the promising extract antioxidant effect. This study highlights, the promising in-vivo giardicidal PGLE activity, that was comparable to metronidazole, thus, the extract would be an ideal strongly recommended treatment for giardiasis. When combined with metronidazole, the extract potentiated its therapeutic effect. Besides, having hepatoprotective, anti-inflammatory, and antioxidant properties, the extract can combat the major side effects of metronidazole therapy.

Role of Magnetic Resonance Imaging in the Monitoring of Patients with Nonalcoholic Fatty Liver Disease: Comparison with Ultrasonography, Lipid Profile, and Body Mass Index.

AIM: The aim of this study was to study the role of magnetic resonance imaging (MRI) in monitoring hepatic fat content in cases of nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: 41 adults (mean age: 39 years, 22 males; 19 females) with NAFLD were included after obtaining approval from the institutional ethics committee. The baseline clinical (weight, body mass index [BMI]) and biochemical parameters, fatty liver grade on ultrasonography (USG), and hepatic fat signal fraction (FSF) using dual-echo chemical shift imaging and proton density fat fraction on magnetic resonance spectroscopy (MRS-PDFF) were assessed, before and after intervention (dietary and lifestyle changes and oral vitamin E for six months). They were categorized into Group A (good compliance to intervention) and Group B (poor compliance), and the clinical and imaging parameters were compared between them. RESULTS: After intervention, Group A (n = 30) showed significant reduction in BMI (28.35 ± 3.25 to 27.14 ± 3.24 kg/m2; P < 0.001), hepatic FSF (19.30 ± 9.09% to 11.18 ± 7.61%; P < 0.05), and MRS-PDFF (18.79 ± 8.53% to 10.64 ± 6.66%). In Group B (n = 11), there was significant increase in BMI (28.85 ± 2.41 to 29.31 ± 2.57 kg/m2; P < 0.001), hepatic FSF (18.96 ± 9.79% to 21.48 ± 11.80%; P < 0.05), and reduction in high-density lipoproteins (P < 0.05). Although there was good correlation between USG and MRS in quantifying liver fat (r = 0.84-0.87; P < 0.001), USG was unable to detect <5.3% change in hepatic fat. There was poor correlation between lipid profile and MRS-PDFF. Change in body weight significantly correlated with change in hepatic fat content (r = 0.76; P < 0.001). CONCLUSION: MRI is useful in accurately quantifying and in monitoring hepatic fat content and is better than clinical and biochemical parameters and USG.

Curcumin incorporated titanium dioxide nanoparticles as MRI contrasting agent for early diagnosis of atherosclerosis- rat model.

MRI is an excellent diagnostic technique for atherosclerosis in a non-invasive manner. Application of contrasting agents can improve its contrast through ionic properties. Macrophages and foam cells produce MCP-1 antibody, the sign of development of atherosclerosis. The work aims to develop novel curcumin incorporated titanium dioxide nanoparticles (CTNPs) conjugated with MCP-1 antibody with the specific targeting capability to macrophage-foam cells as contrasting agent for MRI. In vivo toxicity studies of Curcumin, TNPs and CTNPs were also done in Sprague dawley rats by GGT and ALP assays and found to be normal in comparison with control. Histopathology of aorta confirmed that the compound could not elicit a toxic effect in the target organ. Rats were fed with a high cholesterol diet to develop atherosclerotic foam cells and confirmed by Sudan IV staining and serum cholesterol level. CTNP-MCP-1 was injected into animals through tail vein and MRI scanning was done, gave contrasting images of atherosclerotic aorta in comparison with normal. Thus CTNPs can be used as a cost-effective contrasting tool for diagnosis of atherosclerosis at early stages in view of clinical imaging.

Acrylamide induces a thyroid allostasis-adaptive response in prepubertal exposed rats.

Some endocrine-disrupting chemicals (EDCs) can affect the endocrine system through covalent interactions with specific sites, leading to deregulation of physiological homeostasis. The acrylamide (AA) present in some fried or baked foods is an example of an electrophile molecule that is able to form adducts with nucleophilic regions of nervous system proteins leading to neurological defects. A positive correlation between increased urinary AA metabolite concentration and reduced levels of thyroid hormones (TH) was described in adolescents and young adults. Thus, this study aimed to evaluate whether AA affects the physiology of the hypothalamus-pituitary-thyroid (HPT) axis and the possible repercussions in peripheral TH-target systems. For this, male Wistar rats were exposed to doses of 2.5 or 5.0 mg AA/Kg/day, based on the LOAEL (Lowest Observed Adverse Effect Level) during prepubertal development. The expression of molecular markers of HPT functionality was investigated in the hypothalamus, pituitary, thyroid, heart and liver, as well as the hormonal and lipid profiles in blood samples. Herein, we showed that AA acts as EDCs for thyroid gland function, increasing the transcript expression of several proteins related to TH synthesis and altering hypothalamus-pituitary-thyroid axis homeostasis, an effect evidenced by the higher levels of THs in the serum. Compensatory mechanisms were observed in TH-target tissues, such as an increase in Dio3 mRNA expression in the liver and a reduction in Mct8 transcript content in the hearts of AA-treated rats. Together, these results pointed out an allostatic regulation of the HPT axis induced by AA and suggest that chronic exposure to it, mainly associated with food consumption, might be related to the higher prevalence of thyroid dysfunctions.

Vanadium: Risks and possible benefits in the light of a comprehensive overview of its pharmacotoxicological mechanisms and multi-applications with a summary of further research trends.

BACKGROUND: Vanadium (V) is an element with a wide range of effects on the mammalian organism. The ability of this metal to form organometallic compounds has contributed to the increase in the number of studies on the multidirectional biological activity of its various organic complexes in view of their application in medicine. OBJECTIVE: This review aims at summarizing the current state of knowledge of the pharmacological potential of V and the mechanisms underlying its anti-viral, anti-bacterial, anti-parasitic, anti-fungal, anti-cancer, anti-diabetic, anti-hypercholesterolemic, cardioprotective, and neuroprotective activity as well as the mechanisms of appetite regulation related to the possibility of using this element in the treatment of obesity. The toxicological potential of V and the mechanisms of its toxic action, which have not been sufficiently recognized yet, as well as key information about the essentiality of this metal, its physiological role, and metabolism with certain aspects on the timeline is collected as well. The report also aims to review the use of V in the implantology and industrial sectors emphasizing the human health hazard as well as collect data on the directions of further research on V and its interactions with Mg along with their character. RESULTS AND CONCLUSIONS: Multidirectional studies on V have shown that further analyses are still required for this element to be used as a metallodrug in the fight against certain life-threatening diseases. Studies on interactions of V with Mg, which showed that both elements are able to modulate the response in an interactive manner are needed as well, as the results of such investigations may help not only in recognizing new markers of V toxicity and clarify the underlying interactive mechanism between them, thus improving the medical application of the metals against modern-age diseases, but also they may help in development of principles of effective protection of humans against environmental/occupational V exposure.

Screening of Egyptian obese children and adolescents for insertion/deletion (I/D) polymorphism in angiotensin-converting enzyme gene.

BACKGROUND: /aims: The role of angiotensin-converting enzyme (ACE) gene polymorphism in the development of obesity and hypertension in children has not been widely studied. We aimed to screen Egyptian obese children and adolescents for insertion/deletion (I/D) polymorphism in the ACE gene. METHODS: One hundred forty-two children and adolescents were included (70 with simple obesity and 72 controls). Blood pressure was measured, and anthropometric parameters were assessed in all included children and adolescents. Fasting lipid profile, fasting glucose, and insulin were measured. DNA extraction and ACE I/D polymorphism genotyping were also performed. RESULTS: Obese children had a higher frequency of DD genotype (30% in obese versus 11.1% in controls, P = .01) and D alleles (61.8% in obese versus 48.6% in controls, P = .01). Obese children with hypertension and prehypertension had higher frequency of DD genotype than II genotype and higher D alleles than I alleles. DD genotype and D allele were independently associated with hypertension (OR: 9.86 and 11.57, respectively, P < .001), while dyslipidemia and insulin resistance were not associated with the ACE I/D gene polymorphism. CONCLUSION: DD genotype and D-allele of the ACE gene polymorphism were associated with obesity and with hypertension and pre-hypertension in Egyptian children.

Red blood cells membrane micropolarity as a novel diagnostic indicator of type 1 and type 2 diabetes.

Classification of the category of diabetes is extremely important for clinicians to diagnose and select the correct treatment plan. Glycosylation, oxidation and other post-translational modifications of membrane and transmembrane proteins, as well as impairment in cholesterol homeostasis, can alter lipid density, packing, and interactions of Red blood cells (RBC) plasma membranes in type 1 and type 2 diabetes, thus varying their membrane micropolarity. This can be estimated, at a submicrometric scale, by determining the membrane relative permittivity, which is the factor by which the electric field between the charges is decreased relative to vacuum. Here, we employed a membrane micropolarity sensitive probe to monitor variations in red blood cells of healthy subjects (n=16) and patients affected by type 1 (T1DM, n=10) and type 2 diabetes mellitus (T2DM, n=24) to provide a cost-effective and supplementary indicator for diabetes classification. We find a less polar membrane microenvironment in T2DM patients, and a more polar membrane microenvironment in T1DM patients compared to control healthy patients. The differences in micropolarity are statistically significant among the three groups (p<0.01). The role of serum cholesterol pool in determining these differences was investigated, and other factors potentially altering the response of the probe were considered in view of developing a clinical assay based on RBC membrane micropolarity. These preliminary data pave the way for the development of an innovative assay which could become a tool for diagnosis and progression monitoring of type 1 and type 2 diabetes.

Whole-Exome Sequencing Identifies a Variant in Phosphatidylethanolamine N-Methyltransferase Gene to be Associated With Lean-Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIM: Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases with simple steatosis on one end and hepatocellular carcinoma on the other. Although obesity is a known risk factor for NAFLD, individuals with normal body mass index (BMI) also have hepatic fatty infiltration, now termed "lean-NAFLD". It represents a distinct entity with a strong underlying genetic component. The present study aimed to sequence the complete exonic regions of individuals with lean-NAFLD to identify germline causative variants associated with disrupted hepatic fatty acid metabolism, thereby conferring susceptibility to NAFLD. METHODS: Whole blood was collected from patients with lean-NAFLD (n = 6; BMI < 23.0 kg/m2) and matched lean controls (n = 2; discovery set). Liver fat was assessed using acoustic radiation force impulse (ARFI) imaging. Patients with ultrasound-detected NAFLD (n = 191) and controls (n = 105) were part of validation set. DNA was isolated, and whole-exome sequencing (WES) was performed in the discovery cohort (Ion Proton™; Ion AmpliSeq™ Exome RDY Kit). Data were analyzed (Ion Reporter software; Life Technologies), and variants identified. Validation of variants was carried out (Taqman probes; Real time-PCR). Student's t test and Fisher's exact test were used to analyze the statistical significance. RESULTS: Although WES identified ∼74,000 variants in individual samples, using various pipelines. variants in genes namely phosphatidylethanolamine N-methyltransferase (PEMT) and oxysterol-binding protein-related protein10 (OSBPL10) that have roles in dietary choline intake and regulation of cholesterol homeostasis, respectively, were identified (discovery set). Furthermore, significant differences were noted in BMI (p = 0.006), waist/hip circumference (p > 0.001), waist/hip ratio (p > 0.001), aspartate aminotransferase (p > 0.001), alanine aminotransferase (p > 0.001), and triglycerides (p = 0.002) between patients and controls. Validation of variants (rs7946-PEMT and rs2290532-OSBPL10) revealed that variant in PEMT but not OSBPL10 gene was associated (p = 0.04) with threefold increased risk of NAFLD in lean individuals. CONCLUSION: Our results demonstrate the association of rs7946 with lean-NAFLD. WES may be an effective strategy to identify causative variants underlying lean-NAFLD.

Data on association of mitochondrial heteroplasmy and cardiovascular risk factors: Comparison of samples from Russian and Mexican populations.

Despite the fact that the role of mitochondrial genome mutations in a number of human diseases is widely studied, the effect of mitochondrial heteroplasmy in the development of cardiovascular disease has not been adequately investigated. In this study, we compared the heteroplasmy levels of mtDNA from leukocytes for m.3256C>T, m.3336T>C, m.12315G>A, m.5178C>A, m.13513G>A, m.14459G>A, m.14846G>A, m.15059G>A, m.652insG and m.1555A>G mutations in CVD-free subjects and CVD patients in samples derived from Russian and Mexican populations. It was demonstrated that heteroplasmy level of m.5178C>A was associated with CVD in Russian men, and m.14459G>A - in Russian women. Mitochondrial heteroplasmy level of m.13513G>A and m.652insG were associated with CVD in Mexican men, and only m.652insG- in Mexican women. The levels of heteroplasmy for mitochondrial mutations m.3336T>C, m.5178C>A, m.14459G>A, m.14846G>A and m.1555A>G were significantly higher in CVD-free Mexican men, and for m.3256C>T, m.3336T>C, and m.14459G>A - in CVD-free Mexican women.

Preliminary clinical assessment and non- toxicity evaluation of an ayurvedic formulation BGR-34 in NIDDM.

In view of the overall health impact of NIDDM, inventers understand the necessity of improving glycemic control in adults with type 2 diabetes. BGR-34 provides an effective treatment option for adults with type 2 diabetes who have been inadequately controlled on lifestyle with or without other oral hypoglycemic agents (OHGAs) such as metformin, sulfonylurea, or a glitazones. BGR-34 is an appropriate option to consider for addition to a managed care drug formulary. Treatment with BGR-34 produced clinically relevant and statistically significant reductions in all three key measures of glucose control studied -FPG, PPBG and HbA1c- when compared with placebo. BGR-34, showed the promising result with respect to glycemic parameters in NIDDM patient with a significant reduction in fasting blood sugar by 34.3%, postprandial blood sugar 35.5% & glycosylated haemoglobin by 20.31% as compared to placebo group showing a reduction by 13.2%, 10.9% & 10.87% respectively. The trial has also been registered to CTRI, India. This study has been registered in the clinical trial registry-India.

Metabolomic profiling identifies potential pathways involved in the interaction of iron homeostasis with glucose metabolism.

OBJECTIVE: Elevated serum ferritin has been linked to type 2 diabetes (T2D) and adverse health outcomes in subjects with the Metabolic Syndrome (MetS). As the mechanisms underlying the negative impact of excess iron have so far remained elusive, we aimed to identify potential links between iron homeostasis and metabolic pathways. METHODS: In a cross-sectional study, data were obtained from 163 patients, allocated to one of three groups: (1) lean, healthy controls (n = 53), (2) MetS without hyperferritinemia (n = 54) and (3) MetS with hyperferritinemia (n = 56). An additional phlebotomy study included 29 patients with biopsy-proven iron overload before and after iron removal. A detailed clinical and biochemical characterization was obtained and metabolomic profiling was performed via a targeted metabolomics approach. RESULTS: Subjects with MetS and elevated ferritin had higher fasting glucose (p < 0.001), HbA1c (p = 0.035) and 1 h glucose in oral glucose tolerance test (p = 0.002) compared to MetS subjects without iron overload, whereas other clinical and biochemical features of the MetS were not different. The metabolomic study revealed significant differences between MetS with high and low ferritin in the serum concentrations of sarcosine, citrulline and particularly long-chain phosphatidylcholines. Methionine, glutamate, and long-chain phosphatidylcholines were significantly different before and after phlebotomy (p < 0.05 for all metabolites). CONCLUSIONS: Our data suggest that high serum ferritin concentrations are linked to impaired glucose homeostasis in subjects with the MetS. Iron excess is associated to distinct changes in the serum concentrations of phosphatidylcholine subsets. A pathway involving sarcosine and citrulline also may be involved in iron-induced impairment of glucose metabolism.

Can APOE and MTHFR polymorphisms have an influence on the severity of cardiovascular manifestations in Italian Pseudoxanthoma elasticum affected patients?

BACKGROUND: The clinical phenotype of Pseudoxanthoma elasticum (PXE) affected patients, although progressive with age, is very heterogeneous, even in the presence of identical ABCC6 mutations, thus suggesting the occurrence of modifier genes. Beside typical skin manifestations, the cardiovascular (CV) system, and especially the peripheral vasculature, is frequently and prematurely compromised. METHODS AND RESULTS: A cohort of 119 Italian PXE patients has been characterized for apolipoprotein E (APOE) and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms by PCR. The severity of the clinical phenotype has been quantified according to the Phenodex PXE International score system. Statistical analysis (chi2 test, odd ratio, regression analysis, analysis of variance) were done by GraphPad. Data demonstrate that the frequency of APOE alleles is similar in PXE patients and in healthy subjects and that the allelic variant E2 confers a protection against the age-related increase of CV manifestations. By contrast, PXE patients are characterized by high frequency of the MTHFR-T677T polymorphism. With age, CV manifestations in T677T, but also in C677T, patients are more severe than those associated with the C677C genotype. Interestingly, compound heterozygosity for C677T and A1298C polymorphisms is present in 70% of PXE patients. CONCLUSIONS: PXE patients may be screened for these polymorphisms in order to support clinicians for a better management of disease-associated CV complications.

Biophysical analysis of the interaction of the serum protein human ß2GPI with bacterial lipopolysaccharide.

There are several human serum proteins for which no clear role is yet known. Among these is the abundant serum protein beta2-glycoprotein-I (ß2GPI), which is known to bind to negatively charged phospholipids as well as to bacterial lipopolysaccharides (LPS), and was therefore proposed to play a role in the immune response. To understand the details of these interactions, a biophysical analysis of the binding of ß2GPI to LPS and phosphatidylserine (PS) was performed. The data indicate only a moderate tendency of the protein (1) to influence the LPS-induced cytokine production in vitro, (2) to react exothermally with LPS in a non-saturable way, and (3) to change its local microenvironment upon LPS association. Additionally, we found that the protein binds more strongly to phosphatidylserine (PS) than to LPS. Furthermore, ß2GPI converts the LPS bilayer aggregates into a stronger multilamellar form, and reduces the fluidity of the hydrocarbon moiety of LPS due to a rigidification of the acyl chains. From these data it can be concluded that ß2GPI plays a role as an immune-modulating agent, but there is much less evidence for a role in immune defense against bacterial toxins such as LPS.

Successful Treatment of Rapid Onset, Symptomatic de novo Non-alcoholic Steatohepatitis Following Liver Transplantation: A Case Report.

A 45 year old female with a body mass index (BMI) of 24 underwent successful liver transplantation (LT) for alcoholic cirrhosis using a donor liver from an obese woman with microvesicular steatosis (80%) and minimal macrovesicular steatosis (5-10%) on liver biopsy. Ascites and hepatosplenomegaly developed soon after LT with progressive increase of serum alkaline phosphatase to 1340 IU/L while aspartate aminotransferase (AST), and alanine transaminase (ALT), and total bilirubin remained normal. Imaging showed marked hepatomegaly, extensive fatty infiltration of the liver, and compression of the hepatic veins with narrowing of the intrahepatic inferior vena cava (IVC). Liver biopsy on post-operative day 39 revealed 90-100% macrovesicular steatosis, steatohepatitis, and portal fibrosis. A hepatic venogram showed a 10 cm segment of intrahepatic IVC stenosis that was stented, improving portal venous pressure measurements. However, portal hypertension requiring diuretic therapy and multiple paracenteses remained. By 3 months after LT, her liver had grown to 22 cm, transaminases increased 2-4 times the upper limit of normal with a 2:1 AST to ALT ratio. Liver biopsy at post-LT day 82 showed no change in steatosis and steatohepatitis despite corticosteroid withdrawal and interval periportal and perisinusoidal fibrosis. 12 weeks after LT, the patient was found to have low apolipoprotein B (65 mg/dL), high-density lipoprotein (HDL) (<10 mg/dL), low-density lipoproteins (LDL) (9 mg/dL), and total cholesterol (<50 mg/dL) levels. Therapy was started for NASH with high dose (800 IU daily) vitamin E and pioglitazone 15 mg daily, and she received topical vegetable oil and oral essential fatty acid supplements. Liver enzymes normalized after 3 months and her lipid profile improved markedly (HDL 27 mg/dL, total cholesterol 128 mg/dL), with progressive decrease in liver size and resolution of ascites after 5 months of therapy. At 2 years post-LT, the liver enzymes remain normal and lipids have normalized.